Deficiency of estrogens during menopause can lead to a number of complications including hot flushes, reduced bone density, mood swings, etc. These symptoms are commonly treated with synthetic hormones. Although the rate of bone density reduction can be alleviated, hormone replacement therapy (HRT) was discovered to be associated with increased cardiovascular disorders in one of the largest studies of its kind (Women's health Initiative, WHI) (Seelig, Altura et al. 2004). HRT was also linked to increased risk of breast and ovarian cancer (Fernandez, Gallus et al. 2003, Gambacciani, Monteleone et al. 2003). After the WHI trial results were published, the use of HRT was reduced dramatically. Many postmenopausal women have resorted to alternative therapy because phytoestrogens are generally considered to be safe and efficacious. The use of soy and Red clover (Trifolium pratense), which are rich in phytoestrogens, has been on the rise (Beck, Rohr et al. 2005). Despite the trend, clinical trial results on phytoestrogens, however, have been equivocal (Beck, Rohr et al. 2005, Booth, Piersen et al. 2006, Wuttke, Jarry et al. 2007, Ma, Qin et al. 2008). Alternative therapy has not replaced HRT effectively. A recent study showed that the trend of women moving away from HRT has led to an alarming increase in bone fractures and it is estimated that fractures related to menopause is expected to exceed 40,000 per year in women aged 65-69 years (Gambacciani, Ciaponi et al. 2007). Since the side effects of HRT were publicized after the WHI trial, it has since been reevaluated. There is no consensus with regard to HRT's safety among the medical research community. Therefore, a much closer look at the ‘less than expected’ effects of phytoestrogens should be undertaken because the toxicity profile of this type of products is so much more favorable.
The major bioactive isoflavones in soy are genistein, daidzein, glycitein and prunetin (Setchell and Cassidy 1999). They are also present in their glycoside forms. There are three classes of bioactives in red clover: isoflavones, coumestrols and lignans (Beck, Rohr et al. 2005). The quantity of coumestrols and lignans is small; therefore, their contribution to the overall activity is likely minimal. The major isoflavones in red clover are Biochanin A and Formononetin (Liu, Burdette et al. 2001, Overk, Yao et al. 2005, Booth, Overk et al. 2006). Genistein and daidzein are present in minute quantities. Biochanin A and Formononetin are precursors of their respective active moieties, genistein and daidzein. The conversion takes place in the intestine by intestinal flora and liver, although the relative significance has not been established. Daidzein is converted by bacteria in the colon to form a more estrogenic metabolite, equol. In Red clover, a significant quantity of Biochanin A and Formononetin is in the form of glycosides. The glycosides in soy and red clover are converted to their respective aglycones by the intestinal flora before absorption (Setchell and Cassidy 1999).
Relative absorption of isoflavone glycoside and their respective aglycones is a subject of controversy. Although the cause of controversy is not readily apparent, the low solubility of the aglycones in a preparation may have a profound effect on their dissolution, metabolism and absorption.
Formononetin and Biochanin A are de-methylated by the intestinal micro flora to produce two active metabolites daidzein and genistein, respectively (Hur and Rafii 2000). However, the site of this metabolic pathway is questioned (Tolleson, Doerge et al. 2002).
Metabolism of isoflavones is mainly mediated by Phase II enzymes in the enterocytes and hepatocytes. Although metabolism of individual isoflavones in rats has been well characterized (Jia, Chen et al. 2004, Chen, Lin et al. 2005, Chen, Wang et al. 2005), interaction between components has not been evaluated.
Clinical studies show that extracts of red clover or soy are safe; however, their efficacies are also equivocal (Booth, Piersen et al. 2006). Although there are proprietary products in the market, which have shown potentials for treating or preventing postmenopausal osteoporosis, these products unfortunately, do not have the quality of a drug. The major shortcomings for the design of these products in the market are that they have not taken into consideration of the interplay between pharmacokinetics and pharmacodynamics. In other words, proper dosage and/or dosing interval are empirically decided.
In this invention, the interplay between these “active” components is evaluated and quantified using a proprietary physiologically based pharmacokinetic and pharmacodynamic model (PBPKPD).
The dosages of the new products are a small fraction of those available in the market. The advantage of these products is their consistency. By modifying the mode of delivery, the other advantage of this product is the increase in the bioavailability of the aglycones and eliminates the conversion to their respective bioactive metabolites in the colon, which leads to variability in efficacy.